Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)

NCT ID: NCT04965597

Last Updated: 2025-09-05

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-04-19
• Study Completion Date: 2026-03-31

Brief Summary

This phase II trial tests whether treosulfan, fludarabine, and rabbit antithymocyte globulin (rATG) work when given before a blood or bone marrow transplant (conditioning regimen) to cause fewer complications for patients with bone marrow failure diseases. Chemotherapy drugs, such as treosulfan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Fludarabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. rATG is used to decrease the body's immune response and may improve bone marrow function and increase blood cell counts. Adding treosulfan to a conditioning regimen with fludarabine and rATG may result in patients having less severe complications after a blood or bone marrow transplant.

Detailed Description

OUTLINE:

CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and lapine T-lymphocyte immune globulin (rATG) IV over 4-6 hours on days -4 to -2.

TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus orally (PO). Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) as well as possible chest radiography (x-ray) or computed tomography (CT) at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.

After completion of study treatment, patients are followed up at 1 year from transplant.

Conditions

Bone Marrow Failure Syndrome; Congenital Amegakaryocytic Thrombocytopenia; Diamond-Blackfan Anemia; Hereditary Sideroblastic Anemia; Paroxysmal Nocturnal Hemoglobinuria; Shwachman-Diamond Syndrome; Hematologic Neoplasm With Germline GATA2 Mutation; Hematologic Neoplasm With Germline SAMD9 Mutation; Hematologic Neoplasm With Germline SAMD9L Mutation

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2.

TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.

Group Type: EXPERIMENTAL

Treosulfan

Intervention Type: DRUG

Given IV

Fludarabine Phosphate

Intervention Type: DRUG

Given IV

Tacrolimus

Intervention Type: DRUG

Given IV and PO

Methotrexate

Intervention Type: DRUG

Given IV

Lapine T-Lymphocyte Immune Globulin

Intervention Type: BIOLOGICAL

Given IV

Peripheral Blood Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo PBSC

Allogeneic Bone Marrow Transplantation

Intervention Type: PROCEDURE

Undergo bone marrow transplant

Quality-of-Life Assessment

Intervention Type: OTHER

Ancillary studies

Echocardiography

Intervention Type: PROCEDURE

Undergo ECHO

Multigated Acquisition Scan

Intervention Type: PROCEDURE

Undergo MUGA

Bone Marrow Biopsy

Intervention Type: PROCEDURE

Undergo bone marrow biopsy and aspiration

Bone Marrow Aspiration

Intervention Type: PROCEDURE

Undergo bone marrow biopsy and aspiration

Biospecimen Collection

Intervention Type: PROCEDURE

Undergo blood sample collection

X-Ray Imaging

Intervention Type: PROCEDURE

Undergo chest x-ray

Computed Tomography

Intervention Type: PROCEDURE

Undergo chest CT

Interventions

Treosulfan

Given IV

Intervention Type: DRUG

Fludarabine Phosphate

Given IV

Intervention Type: DRUG

Tacrolimus

Given IV and PO

Intervention Type: DRUG

Methotrexate

Given IV

Intervention Type: DRUG

Lapine T-Lymphocyte Immune Globulin

Given IV

Intervention Type: BIOLOGICAL

Peripheral Blood Stem Cell Transplantation

Undergo PBSC

Intervention Type: PROCEDURE

Allogeneic Bone Marrow Transplantation

Undergo bone marrow transplant

Intervention Type: PROCEDURE

Quality-of-Life Assessment

Ancillary studies

Intervention Type: OTHER

Echocardiography

Undergo ECHO

Intervention Type: PROCEDURE

Multigated Acquisition Scan

Undergo MUGA

Intervention Type: PROCEDURE

Bone Marrow Biopsy

Undergo bone marrow biopsy and aspiration

Intervention Type: PROCEDURE

Bone Marrow Aspiration

Undergo bone marrow biopsy and aspiration

Intervention Type: PROCEDURE

Biospecimen Collection

Undergo blood sample collection

Intervention Type: PROCEDURE

X-Ray Imaging

Undergo chest x-ray

Intervention Type: PROCEDURE

Computed Tomography

Undergo chest CT

Intervention Type: PROCEDURE

Other Intervention Names

Dihydroxybusulfan; Ovastat; Treosulphan; Tresulfon; Trecondi; 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; 9H-purin-6-amine; 2-fluoro-9-(5-O-phosphono-beta-D-arabinofuranosyl); Beneflur; Fludara; Fludarabine-5'-Monophosphate; SH T 586; FK 506; Fujimycin; Hecoria; Prograf; Protopic; Abitrexate; Alpha-Methopterin; Amethopterin; Brimexate; Emthexat; Emtexate; Farmitrexat; Methotrexate LPF; Methylaminopterin; Methotrexatum; Metotrexato; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; Anti-Thymocyte Globulin Rabbit; Grafalon; Rabbit Anti-Human Thymocyte Globulin (RATG); Rabbit Anti-Thymocyte Globulin; Rabbit Antithymocyte Globulin; Rabbit ATG; rATG; Thymoglobulin; Antithymocyte globulin rabbit ATG; Imtix; PBPC transplantation; PBSCT; Peripheral Blood Progenitor Cell Transplantation; PERIPHERAL BLOOD STEM CELL TRANSPLANT; peripheral stem cell support; Peripheral Stem Cell Transplant; peripheral stem cell transplantation; Allo BMT; Allogeneic Blood and Marrow Transplantation; Allogeneic BMT; Quality of Life Assessment; EC; Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; Gated Heart Pool Scan; MUGA; Multi-Gated Acquisition Scan; MUGA Scan; Radionuclide Ventriculogram Scan; Radionuclide ventriculography; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; Biological Sample Collection; Conventional X-Ray; Diagnostic Radiology; Computed Axial Tomography; CAT Scan; CT Scan

Eligibility Criteria

Inclusion Criteria

• Patient must be >= 1.0 year of age and less than 50.0 years of age at the time of enrollment (i.e. patient must have celebrated their 1st birthday when enrolled and must NOT have celebrated their 50th birthday when enrolled; 49.99 years)
• Underlying BMFD treatable by allogenic HCT
• Shwachman-Diamond syndrome

• Criteria for Diagnosis:

• A pathogenic mutation(s) for Shwachman-Diamond syndrome
• For those patients tested but lacking a genetic mutation they must meet both *** criteria below:

• Exocrine pancreatic dysfunction as defined by at least one of the following:

• Pancreatic isoamylase below normal (age >= 3 years old), OR
• Fecal elastase < 200, AND
• Bone marrow failure as evidence by at least one of the following:

• Intermittent or persistent neutropenia (absolute neutrophil count < 1,500/uL), OR
• Hypo-productive anemia with a hemoglobin concentration below the age-related adjusted norms, OR
• Unexplained macrocytosis, OR
• Platelet count < 150,000/uL without alternative etiology, OR
• Hypocellular bone marrow
• Indications for HCT:

• Severe neutropenia (absolute neutrophil count [ANC] < 500/uL), OR
• Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR
• Severe thrombocytopenia (platelet count < 20,000/uL) or transfusion-dependent thrombocytopenia, OR
• Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 eligibility review committee (ERC). In addition, patients with severe or recurrent infections will be reviewed by the ERC if they do not meet the indications for transplant listed above
• Diamond Blackfan Anemia

• Criteria for Diagnosis:

• A pathogenic mutation for Diamond Blackfan anemia
• For those patients tested but lacking a genetic mutation the patient must meet the first *** criteria and at least one of the subsequent *** criteria listed below:

• History of deficiency of erythroid precursors in an otherwise cellular bone marrow AND,
• Reticulocytopenia, OR
• Elevated adenosine deaminase activity, OR
• Elevated hemoglobin F, OR
• Macrocytosis, OR
• Congenital anomalies
• Indications for HCT:

• Red blood cell (RBC) transfusion dependent anemia despite an adequate trial of steroids; OR
• Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC
• Congenital Sideroblastic anemia

• Criteria for Diagnosis:

• A pathogenic mutation(s) for sideroblastic anemia
• For those patients tested but lacking a genetic mutation:

• Presence of ringed sideroblasts in the bone marrow excluding acquired causes of ringed sideroblasts such as lead poisoning & zinc toxicity
• Indications for HCT:

• Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia OR
• Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC
• GATA2 mutation with associated marrow failure

• Criteria for Diagnosis:

** A pathogenic mutation(s) for GATA2

• Indications for HCT:

• Severe neutropenia (ANC < 500/uL), OR
• Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR
• Severe thrombocytopenia (platelet count < 20,000/uL) or transfusion-dependent thrombocytopenia, OR
• Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC. In addition, patients with severe or recurrent infections will be reviewed by the ERC if they do not meet indications for transplant listed above
• SAMD9 or SAMD9L disorders

• Criteria for Diagnosis:

** A pathogenic mutation(s) for SAMD9 or SAMD9L

• Indications for HCT:

• Severe neutropenia (ANC < 500/uL), OR
• Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR
• Severe thrombocytopenia (platelet count < 20,000/uL) or transfusion-dependent thrombocytopenia, OR
• Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC
• Congenital amegakaryocytic thrombocytopenia

• Criteria for Diagnosis:

• A pathogenic mutation(s) for congenital amegakaryocytic thrombocytopenia.
• For those patients tested but lacking a genetic mutation the patient must meet criteria below:

• Thrombocytopenia early in life, AND
• History of bone marrow demonstrating megakaryocyte hypoplasia
• Indications for HCT:

• Severe thrombocytopenia (platelet count < 20,000/uL) or transfusion-dependent thrombocytopenia, OR
• Neutropenia defined as an ANC < 500/uL, OR
• Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR
• Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC
• Paroxysmal nocturnal hemoglobinuria

• Criteria for Diagnosis:

• Paroxysmal nocturnal hemoglobinuria (PNH) clone size in granulocytes >= 10%, AND
• Complement mediated intravascular hemolysis with an elevated LDH (above institutional upper limits of normal)
• Indications for HCT:

• PNH with thrombosis despite adequate medical management, OR
• PNH with intravascular hemolysis requiring transfusion support despite adequate medical management, OR
• Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC. In addition, patients with PNH and cytopenias may be considered for the protocol eligibility following review by protocol 1904 ERC
• An undefined BMFD: a patient with a BMFD for whom a genetic mutation responsible for their bone marrow failure phenotype has not been identified (excluding PNH) will be eligible for this clinical trial following approval by Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1904 ERC

• A BMFD with a known genetic mutation but not listed above will be eligible for this clinical trial following approval by BMT CTN 1904 ERC
• Patient and/or legal guardian must sign informed consent prior to initiation of conditioning for BMT CTN 1904
• Note: The following patients MUST be reviewed by the BMT CTN 1904 ERC in order to determine if they are eligible for this trial:

• All patients with Shwachman-Diamond syndrome, Diamond Blackfan anemia, congenital sideroblastic anemia, and congenital amegakaryocytic thrombocytopenia who have had genetic testing and a genetic mutation responsible for their disease was not identified
• All patients with an undefined BMFD: a patient with a BMFD for whom a genetic mutation responsible for their bone marrow failure phenotype has not been identified, excluding PNH
• All patients with a BMFD and a known genetic mutation that is not listed above
• All patients with GATA2 mutation and associated marrow failure
• All patients with SAMD9 or SAMD9L disorders
• There may be circumstances where a treating physician will consider a transplant for a patient with a BMFD who does not meet all the criteria listed under "indications for HCT". In these situations, treating physicians may submit their patient to the BMT CTN 1904 ERC for review in order to determine if the patient is eligible for this clinical trial based on additional clinical or laboratory information
• Many patients with BMFD can have bone marrow evaluations that raise concern for possible myelodysplastic syndrome (MDS) including but not limited to dysplastic bone marrow evaluations or cytogenetic abnormalities. However, in patients BMFD these findings are not necessarily diagnostic or consistent with MDS. Therefore, given the complexities of diagnosing MDS in patients with BMFD, all patients with bone marrow evaluations concerning for possible MDS should be submitted to the ERC for review to confirm or exclude MDS. This is particularly important as we do not want to exclude potentially eligible patients due to an incorrect diagnosis of MDS
• HLA-MATCHED RELATED DONOR: HLA-matched sibling: Must be a minimum HLA-6/6 matched to the recipient at HLA-A, -B (serologic typing) and DRB1 (high-resolution typing)
• HLA-MATCHED RELATED DONOR: HLA-matched related (phenotypic match): Fully matched for HLA-A, -B, -C, -DRB1, and DQB1 by high-resolution typing.
• HLA-MATCHED RELATED DONOR: If a genetic mutation is known for the patient, the HLA-matched related donor [either HLA-matched sibling or HLA-matched related (phenotypic match)] must be screened for the same genetic mutation if clinically appropriate and should be confirmed to not have the same genetic disease (this does not include patients with PNH). Consult the protocol team with questions
• HLA-MATCHED RELATED DONOR: If a patient has an undefined BMFD (a patient with a BMFD for whom a genetic mutation responsible for their bone marrow failure phenotype has not been identified), the HLA-matched related donor [either HLA-matched sibling or HLA-matched related (phenotypic match)] must have an evaluation as directed by the treating physician to confirm that the donor does not have the same underlying disease. This will include a complete blood count (CBC) with differential and potentially a bone marrow evaluation or other studies as directed by the treating physician
• UNRELATED DONOR: Fully matched for HLA-A, -B, -C, -DRB1, and DQB1 by high-resolution typing OR
• UNRELATED DONOR: Mismatched for a single HLA-class 1 allele (HLA-A, -B, or -C) by high-resolution typing; OR
• UNRELATED DONOR: Mismatched for a single HLA DQB1 allele or antigen by high-resolution typing

• Note: donor patient (DP) matching per institutional practice
• DONOR SELECTION RECCOMENDATIONS: in the case where there are multiple donor options, donors should be selected based on the following priority numbered below:

• Unaffected fully HLA-matched sibling
• Unaffected fully phenotypically HLA-matched related donor
• Fully HLA-matched unrelated donor
• Unrelated donor with single allele or antigen level mismatch at DQB1
• Unrelated donor with single allele level mismatch at class 1 (HLA-A, -B, or -C)

Exclusion Criteria

• Patients with idiopathic aplastic anemia, Fanconi anemia, dyskeratosis congenita, and congenital neutropenia
• Patients with MDS as defined by the World Health Organization (WHO) or leukemia
• Prior allogeneic HCT
• Patient's weight =< 10.0 kg (actual body weight and adjusted body weight) at time of study enrollment
• Lansky (patients < 16 years of age) or Karnofsky (patients >= 16 years of age) performance < 70%
• Left ventricular ejection fraction < 50% by echocardiogram or multi-gated acquisition (MUGA) scan

• For patients unable to obtain a left ventricular ejection fraction, left ventricular shortening fraction of < 26%
• Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected/adjusted for hemoglobin) < 50%, forced expiratory volume (FEV)1 < 50% predicted, and forced vital capacity (FVC) < 50% predicted
• For patients unable to perform pulmonary function tests (PFTs) due to age or developmental delay: oxygen (O2) saturation < 92% on room air
• On supplemental oxygen
• Estimated creatinine clearance < 60 mL/minute/1.73m^2 (estimated per institutional practice)
• Dialysis dependent
• Conjugated bilirubin > 2 x upper limit of normal for age (ULN, unless attributable to Gilbert's syndrome)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 4 x ULN for age, or
• Fulminant liver failure or cirrhosis
• Iron overload - This exclusion criterion only applies to patients who are considered at risk for hepatic or cardiac iron overload. Therefore, not all patients enrolled on this protocol will undergo formal hepatic or cardiac iron assessment

• For patients with a history of significant transfusions defined as >= 8 packed red blood cell transfusions per year for >= 1 year or have received >= 20 packed red blood cell transfusions (lifetime cumulative) will require formal hepatic and cardiac iron measurement. In addition, patients with a prior history of hepatic or cardiac iron overload will also require formal assessment for iron overload. Patients are excluded if:
• Hepatic iron content >= 8 mg Fe/g dry weight by liver magnetic resonance imaging (MRI) using a validated methodology (such as T2 * MRI or ferriscan) or liver biopsy per institutional practice
• Cardiac iron content < 25 msec by cardiac T2 * MRI
• Uncontrolled bacterial infection within 1 week of study enrollment. Uncontrolled is defined as currently taking medication with no clinical improvement or progression on adequate medical treatment
• Uncontrolled viral or fungal infection within 30 days of study enrollment. Uncontrolled is defined as currently taking medication with no clinical improvement or progression on adequate medical treatment
• Positive for human immunodeficiency virus (HIV)
• Presence of clinically significant anti-donor human leukocyte antigen (HLA)-antibodies per institutional practice
• Prior solid organ transplant
• Patients with prior malignancies except resected non-melanoma skin cancer or treated cervical carcinoma in situ
• Females who are pregnant or breast-feeding
• Females and males of childbearing potential who are unwilling to practice an effective method of contraception or agree to abstinence from the time of signing informed consent through 12 months post-transplant or off tacrolimus whichever is later
• Known hypersensitivity to treosulfan or fludarabine
• Known life-threatening reaction (i.e. anaphylaxis) to Thymoglobulin that would prohibit use for the patient as this study requires use of the Thymoglobulin preparation of anti-thymocyte globulin (ATG)

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 49 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Blood and Marrow Transplant Clinical Trials Network

NETWORK

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

National Marrow Donor Program

OTHER

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Lauri Burroughs, MD

Role: STUDY_CHAIR

Fred Hutch/University of Washington Cancer Consortium

Margaret MacMillan, MD

Role: STUDY_CHAIR

University of Minnesota

Locations

Children's Hospital Los Angeles

Los Angeles, California, United States

Rady Children's Hospital/UCSD

San Diego, California, United States

University of California San Francisco

San Francisco, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Children's Healthcare of Atlanta

Atlanta, Georgia, United States

Johns Hopkins University

Baltimore, Maryland, United States

Boston Children's Hospital

Boston, Massachusetts, United States

University of Michigan Medical Center

Ann Arbor, Michigan, United States

University of Minnesota

Minneapolis, Minnesota, United States

St. Louis Children's Hospital

St Louis, Missouri, United States

Roswell Park Comprehensive Cancer Center

Buffalo, New York, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Cohen Children's Hospital of NY

Queens, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Cincinnati Children's Hospital

Cincinnati, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Oregon Health & Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

MD Anderson Cancer Center

Houston, Texas, United States

Texas Children's Hospital

Houston, Texas, United States

Primary Children's/University of Utah

Salt Lake City, Utah, United States

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, United States

Medical College of Wisconsin/Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

Provided Documents

Document Type: Informed Consent Form

View Document

Other Identifiers

2U10HL069294-11

Identifier Type: NIH

Identifier Source: secondary_id

View Link

RG1121820

Identifier Type: OTHER

Identifier Source: secondary_id

10840

Identifier Type: OTHER

Identifier Source: secondary_id

NCI-2021-13862

Identifier Type: REGISTRY

Identifier Source: secondary_id

BMTCTN1904

Identifier Type: -

Identifier Source: org_study_id